Diabetes is a risk factor for severe periodontal disease. Major pathogens associated with periodontitis are Porphyromonas gingivalis (P. gingivalis), Bacteroides forsythus (B. forsythus) and Treponema denticola (T. denticola), all Gram-negative anaerobes. Previous studies suggest that both innate and adaptive immunity are involved in protection against periodontal infection. Innate immune responses are the first line of defense against an infection. Innate immune system cells, such as macrophages, react to common microbial surface molecules through newly discovered receptors on the macrophage cell surface called Toll-like receptors (TLRs). Preliminary studies have found that lipopolysaccharide (LPS) derived from Gram-negative bacteria regulate the expression of several different TLRs in macrophages and trigger cytokine production and expression of co-stimulatory molecules in macrophages. These events are essential for macrophage activation and initiation of specific adaptive immune responses for generation of antigen specific cells. The purpose of this project is to study innate immunity in type 1 diabetes, in particular, the role of TLR in the initiation of host immune responses against oral pathogens in periodontal infection, using the well established non-obese diabetic (NOD) mouse model of type I diabetes. NOD macrophage responses to live bacteria and LPS isolated from P. gingivalis, B. forsythus and T. denticola in terms of cytokine production, co-stimulatory molecule expression, TLR mRNA levels and TLR signal transduction will be compared to NOR mice, a diabetes resistant control strain. Our hypothesis is that a defect in innate immunity in type 1 diabetes contributes to the susceptibility to periodontal infection since it should be the interaction between the TLR and the oral pathogen that initiates immune responses. These experiments will generate novel information on innate immune responses to oral pathogens in type 1 diabetes and may lead to development of therapeutic interventions to alleviate severe periodontitis in diabetes.